排序方式: 共有15条查询结果,搜索用时 453 毫秒
1.
Parton LE Ye CP Coppari R Enriori PJ Choi B Zhang CY Xu C Vianna CR Balthasar N Lee CE Elmquist JK Cowley MA Lowell BB 《Nature》2007,449(7159):228-232
A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic beta-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (K(ATP)) channels. Although beta-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of K(ATP) channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes. 相似文献
2.
Clarke JT Gérard JC Grodent D Wannawichian S Gustin J Connerney J Crary F Dougherty M Kurth W Cowley SW Bunce EJ Hill T Kim J 《Nature》2005,433(7027):717-719
It has often been stated that Saturn's magnetosphere and aurorae are intermediate between those of Earth, where the dominant processes are solar wind driven, and those of Jupiter, where processes are driven by a large source of internal plasma. But this view is based on information about Saturn that is far inferior to what is now available. Here we report ultraviolet images of Saturn, which, when combined with simultaneous Cassini measurements of the solar wind and Saturn kilometric radio emission, demonstrate that its aurorae differ morphologically from those of both Earth and Jupiter. Saturn's auroral emissions vary slowly; some features appear in partial corotation whereas others are fixed to the solar wind direction; the auroral oval shifts quickly in latitude; and the aurora is often not centred on the magnetic pole nor closed on itself. In response to a large increase in solar wind dynamic pressure Saturn's aurora brightened dramatically, the brightest auroral emissions moved to higher latitudes, and the dawn side polar regions were filled with intense emissions. The brightening is reminiscent of terrestrial aurorae, but the other two variations are not. Rather than being intermediate between the Earth and Jupiter, Saturn's auroral emissions behave fundamentally differently from those at the other planets. 相似文献
3.
Stallard T Miller S Melin H Lystrup M Cowley SW Bunce EJ Achilleos N Dougherty M 《Nature》2008,453(7198):1083-1085
Planetary aurorae are formed by energetic charged particles streaming along the planet's magnetic field lines into the upper atmosphere from the surrounding space environment. Earth's main auroral oval is formed through interactions with the solar wind, whereas that at Jupiter is formed through interactions with plasma from the moon Io inside its magnetic field (although other processes form aurorae at both planets). At Saturn, only the main auroral oval has previously been observed and there remains much debate over its origin. Here we report the discovery of a secondary oval at Saturn that is approximately 25 per cent as bright as the main oval, and we show this to be caused by interaction with the middle magnetosphere around the planet. This is a weak equivalent of Jupiter's main oval, its relative dimness being due to the lack of as large a source of ions as Jupiter's volcanic moon Io. This result suggests that differences seen in the auroral emissions from Saturn and Jupiter are due to scaling differences in the conditions at each of these two planets, whereas the underlying formation processes are the same. 相似文献
4.
A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. 总被引:28,自引:0,他引:28
P J Rosenfeld G S Cowley T L McGee M A Sandberg E L Berson T P Dryja 《Nature genetics》1992,1(3):209-213
Mutations within the rhodopsin gene are known to give rise to autosomal dominant retinitis pigmentosa (RP), a common hereditary form of retinal degeneration. We now describe a patient with autosomal recessive RP who is homozygous for a nonsense mutation at codon 249 within exon 4 of the rhodopsin gene. This null mutation, the first gene defect identified in autosomal recessive retinitis pigmentosa, should result in a functionally inactive rhodopsin protein that is missing the sixth and seventh transmembrane domains including the 11-cis-retinal attachment site. We also found a different null mutation carried heterozygously by an unrelated unaffected individual. Heterozygous carriers of either mutation had normal ophthalmologic examinations but their electroretinograms revealed an abnormality in rod photoreceptor function. 相似文献
5.
Alexander Negoda Elizabeth A. Cowley Yassine El Hiani Paul Linsdell 《Cellular and molecular life sciences : CMLS》2018,75(16):3027-3038
Cystic fibrosis can be treated by potentiators, drugs that interact directly with the cystic fibrosis transmembrane conductance regulator (CFTR) Cl? channel to increase its open probability. These substances likely target key conformational changes occurring during channel opening and closing, however, the molecular bases of these conformational changes, and their susceptibility to manipulation are poorly understood. We have used patch clamp recording to identify changes in the three-dimensional organization of the extracellularly accessible parts of the CFTR protein during channel opening and closing. State-dependent formation of both disulfide bonds and Cd2+ bridges occurred for pairs of cysteine side-chains introduced into the extreme extracellular ends of transmembrane helices (TMs) 1, 6, and 12. Between each of these three TMs, we found that both disulfide bonds and metal bridges formed preferentially or exclusively in the closed state and that these inter-TM cross-links stabilized the closed state. These results indicate that the extracellular ends of these TMs are close together when the channel is closed and that they separate from each other when the channel opens. These findings identify for the first time key conformational changes in the extracellular parts of the CFTR protein that can potentially be manipulated to control channel activity. 相似文献
6.
Pryor WR Rymer AM Mitchell DG Hill TW Young DT Saur J Jones GH Jacobsen S Cowley SW Mauk BH Coates AJ Gustin J Grodent D Gérard JC Lamy L Nichols JD Krimigis SM Esposito LW Dougherty MK Jouchoux AJ Stewart AI McClintock WE Holsclaw GM Ajello JM Colwell JE Hendrix AR Crary FJ Clarke JT Zhou X 《Nature》2011,472(7343):331-333
Although there are substantial differences between the magnetospheres of Jupiter and Saturn, it has been suggested that cryovolcanic activity at Enceladus could lead to electrodynamic coupling between Enceladus and Saturn like that which links Jupiter with Io, Europa and Ganymede. Powerful field-aligned electron beams associated with the Io-Jupiter coupling, for example, create an auroral footprint in Jupiter's ionosphere. Auroral ultraviolet emission associated with Enceladus-Saturn coupling is anticipated to be just a few tenths of a kilorayleigh (ref. 12), about an order of magnitude dimmer than Io's footprint and below the observable threshold, consistent with its non-detection. Here we report the detection of magnetic-field-aligned ion and electron beams (offset several moon radii downstream from Enceladus) with sufficient power to stimulate detectable aurora, and the subsequent discovery of Enceladus-associated aurora in a few per cent of the scans of the moon's footprint. The footprint varies in emission magnitude more than can plausibly be explained by changes in magnetospheric parameters--and as such is probably indicative of variable plume activity. 相似文献
7.
Whyte WA Bilodeau S Orlando DA Hoke HA Frampton GM Foster CT Cowley SM Young RA 《Nature》2012,482(7384):221-225
8.
即使应激极其有害并且谁也无法加以摆脱但我们也并非注定都要身受其害。精神病专家其比杰尔认为,“企求无应激的生活是不合情理的目标应当是能主动地、有效地对付应激。”事乡上,任何人都可以学会更好地对付应激反应的方法。一种方法是向能天然地抵抗应激的人学习有的人历经磨难——被捕、酷刑、疾病、失共——而仍能以少有的宁静心泰然处之。从他们安上可以发现一种与众不同的想事习惯。他们倾6于关注直接面对的问题(如对一个行将死去的蔡子的慰藉),而不是想得太多太全面(如即将发生的死亡)。他们还会找到自我解释的方法——如长他… 相似文献
9.
Williams RB Cotsapas CJ Cowley MJ Chan E Nott DJ Little PF 《Nature genetics》2006,38(8):855-6; author reply 856-9
10.
Garfield AS Cowley M Smith FM Moorwood K Stewart-Cox JE Gilroy K Baker S Xia J Dalley JW Hurst LD Wilkinson LS Isles AR Ward A 《Nature》2011,469(7331):534-538
Imprinted genes, defined by their preferential expression of a single parental allele, represent a subset of the mammalian genome and often have key roles in embryonic development, but also postnatal functions including energy homeostasis and behaviour. When the two parental alleles are unequally represented within a social group (when there is sex bias in dispersal and/or variance in reproductive success), imprinted genes may evolve to modulate social behaviour, although so far no such instance is known. Predominantly expressed from the maternal allele during embryogenesis, Grb10 encodes an intracellular adaptor protein that can interact with several receptor tyrosine kinases and downstream signalling molecules. Here we demonstrate that within the brain Grb10 is expressed from the paternal allele from fetal life into adulthood and that ablation of this expression engenders increased social dominance specifically among other aspects of social behaviour, a finding supported by the observed increase in allogrooming by paternal Grb10-deficient animals. Grb10 is, therefore, the first example of an imprinted gene that regulates social behaviour. It is also currently alone in exhibiting imprinted expression from each of the parental alleles in a tissue-specific manner, as loss of the peripherally expressed maternal allele leads to significant fetal and placental overgrowth. Thus Grb10 is, so far, a unique imprinted gene, able to influence distinct physiological processes, fetal growth and adult behaviour, owing to actions of the two parental alleles in different tissues. 相似文献